The connection subdomain and RNase H domain of HIV-1 RT have recently been implicated in the emergence of HIV-1 strains that are resistant to NRTI and NNRTI drugs. Site-specific mutations in the connection subdomain and RNase H domain reportedly affect substrate or NRTI binding affinity and other polymerase-related properties such as processivity, suggesting that definitive long-distance cross-talk occurs between the polymerase domain and these two distantly located structural units of HIV-1 RT. Numerous mechanisms, including a reduction in RNase H cleavage activity, which decreased template switching, and improper positioning of template-primer substrate have been proposed to explain the drug-resistant mutations. Based on the three-dimensional (3D) structure of HIV-1 RT, we propose that hydrophobic residues at the C-terminal region of the RNase H domain interacting with the C-terminal connection subdomain may be structurally important in subunit dimerization; any mutational changes in these regions may affect dimer stability and the substrate binding affinity of HIV-1 RT. We propose to investigate the implications of mutations of hydrophobic residues at the interface of the connection subdomain and RNase H domain of HIV-1 RT with respect to dimer stability and drug sensitivity of the enzyme. We will also include clinically relevant drug-resistant mutations that emerge in connection and RNase H under drug pressure.